Periprocedural thromboprophylaxis in patients receiving chronic anticoagulation therapy

Curriculum in Cardiology Periprocedural thromboprophylaxis in patients receiving chronic anticoagulation therapy Syed M. Jafri, MD, FACC Detroit, Mich Patients receiving chronic anticoagulation therapy pose a clinical challenge when therapy needs to be interrupted for surgical or invasive procedures. Maintaining anticoagulation places them at risk for serious bleeding complications, whereas discontinuing anticoagulation puts them at risk of thromboembolic complications. Most patients can undergo dental procedures, cataract surgery, and diagnostic endoscopy without discontinuing anticoagulation. The main patient groups that may require a periprocedural alternative to oral anticoagulation (periprocedural thromboprophylaxis or bridging) include patients with prosthetic heart valves, atrial fibrillation, and hypercoagulable states and patients with chronic venous thrombosis who are undergoing surgery. Currently, there is little consensus on the appropriate perioperative treatment of patients on long-term warfarin therapy. There are an increasing number of studies that evaluate the benefits of periprocedural bridging with low-molecular-weight heparin (LMWH) in place of unfractionated heparin (UFH). An advantage of LMWH over UFH is that perioperative conversion from warfarin therapy with LMWH can be carried out in the outpatient setting, which is more convenient for patients and is cost effective. As with the use of UFH, there are reports of maternal thromboembolic complications with LMWHs in pregnant women with mechanical heart valves. This review brings together the available data on periprocedural bridging to assess the available options for patients on long-term warfarin therapy who are undergoing surgical procedures. It provides a rationale for using LMWHs while individualizing the risks versus benefits in a given patient population. (Am Heart J 2004;147:3 15.) Periprocedural thromboprophylaxis (or bridging) is a common problem for clinicians. To bridge or not to bridge, that s the question. Chronic anticoagulation therapy with warfarin decreases hypercoagulability. 1 Patients receiving chronic anticoagulation therapy pose a clinical challenge when therapy needs to be interrupted for surgical or invasive procedures. Maintaining anticoagulation places them at risk for serious bleeding complications, whereas discontinuing anticoagulation puts them at risk for thromboembolic complications. In addition, surgical procedures increase the risk of venous thrombosis. 2,3 Postoperative anticoagulation with intravenous (iv) heparin is estimated to increase the risk of major bleeding episodes by 3%. 2 In deciding whether to bridge or not to bridge, the risks of bleeding must be weighed against the risk of thromboembolism on a case-by-case basis. 2 The main patient groups that may require a periprocedural alternative to oral anticoagulation include patients with prosthetic heart valves, atrial fibrillation, and hypercoagulable states, and patients with chronic venous thrombosis who are undergoing surgery. There From the Department of Cardiology, Henry Ford Hospital, Detroit, Mich. Submitted November 5, 2002; accepted June 30, 2003. Reprint requests: S. Jafri, MD, FACC, Department of Cardiology, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202. E-mail: SJAFRI2@hfhs.org 0002-8703/$ - see front matter 2004, Elsevier Inc. All rights reserved. doi:10.1016/j.ahj.2003.06.001 is no consensus on the appropriate perioperative management of anticoagulation for patients who have been receiving long-term warfarin therapy. 2 In the most recent American College of Chest Physicians (ACCP) recommendations, periprocedural bridging is graded as 2C (ie, risk/benefit unclear observational studies very weak recommendations). 4 There are reports of expanding the indications for periprocedural bridging with low-molecular-weight heparins (LMWHs) in an outpatient setting. This approach has appeal because of the ease of administration, better pharmacokinetic profile, and cost-effective strategy compared with the inpatient unfractionated heparin (UFH) therapy, which is currently administered to patients who are at moderate to high risk of thromboembolism. This review is an attempt to bring together all the available data on periprocedural bridging to assess the available options for patients who are undergoing surgical procedures and to provide a rationale for using LMWHs while individualizing the risks versus benefits in a given patient. It provides information on when to bridge and how to bridge. For this review, a PubMed search was performed with these search terms: periprocedural anticoagulation and warfarin, chronic anticoagulation and prosthetic heart valves, anticoagulant and dental surgery/ophthalmic surgery/intraocular lenses/cataract surgery/retinal surgery/gastrointestinal endoscopy/prostate surgery/atrial fibrillation/prosthetic heart valves, ophthalmic surgery and warfarin, LMWH, and periprocedural/mechanical

4 Jafri American Heart Journal January 2004 heart valves. Information was also extrapolated from scientific peer-reviewed articles on the perioperative management of anticoagulation. Bleeding potential during surgical procedures Different surgical procedures present their own bleeding risks. Minimally invasive procedures are considered to be associated with a low bleeding risk, whereas during major surgery, patients are at a high risk of bleeding. 5 Factors such as the location and extent of surgery and the accessibility of the bleeding site to compression or other physical means of controlling bleeding strongly influence management. 6 Periprocedural treatment of patients who are receiving long-term anticoagulation therapy and decisions as to whether to continue, substitute, or withhold oral anticoagulation should be tailored to specific surgical procedures. A careful assessment of the bleeding risks in the postoperative state is critical to decide the optimal postoperative bridging protocol. Patients who are at high risk of bleeding can be given prophylactic doses of UFH or LMWH subcutaneously (sc), and, in other patients, compressive devices can be substituted to prevent venous thromboembolism (VTE). Dental surgery Dental procedures represent a particularly common intervention for patients who are receiving continuous anticoagulant therapy. Many physicians recommend interruption of anticoagulant therapy for dental surgery to prevent hemorrhage. However, there are no well-documented cases of serious bleeding problems from dental surgery in patients receiving therapeutic levels of warfarin, whereas serious embolic complications have occurred when warfarin therapy has been withdrawn. 7 A review of the literature showed that serious embolic complications, including death, were 3-times more likely to occur in patients whose anticoagulant therapy was interrupted than were bleeding complications when anticoagulant therapy was continued. 8 Data from 26 study reports showed that, of 774 patients who continued oral anticoagulation therapy during 2014 procedures, only 12 patients (1.6%) had bleeding that could not be controlled with local measures, and most of these patients had an international normalized ratio (INR) higher than the therapeutic range. Of 493 patients who discontinued receiving warfarin during 542 procedures, 5 patients (1.0%) had a thromboembolism, which was fatal in 4 cases. 7 Thus, dental extractions can be performed with minimal risk in patients who are receiving therapeutic or higher levels of anticoagulation. Importantly, when bleeding does occur during or after dental surgery, it can be treated with local measures. In patients undergoing multiple tooth extractions or extensive oral surgery that increases the bleeding risk, procedures can be performed with an INR 1.5. When there is a need to control local bleeding, tranexamic acid or epsilon amino caproic acid mouthwash has been used successfully without the interruption of anticoagulant therapy. 9,10 Ophthalmic surgery Ophthalmic surgical procedures, with the exception of major lid and orbital surgery, are usually associated with minimal blood loss. A survey carried out in 1985 showed that of 135 surgeons in the United States, 75% routinely discontinued anticoagulation 3 to 5 days before cataract surgery. Two deaths and 7 non-fatal thromboembolic episodes were reported by these surgeons. However, no complications of surgery were reported by the surgeons who continued anticoagulation therapy. 11 The safety of performing most ophthalmic surgery while the patient is undergoing therapeutic anticoagulation was subsequently demonstrated in a study of 41 patients receiving long-term anticoagulation therapy who were undergoing 50 surgical procedures (cataract extraction [n 33], vitreoretinal surgery, trabeculectomy, everting lid sutures, intraocular lens implant, trans-septal orbital biopsy). In patients who were receiving anticoagulation therapy at the time of surgery, there were no significant bleeding complications. 12 Although there are no reports of an affect on long-term visual acuity with the continuation of warfarin therapy during surgery, bleeding in the anterior eye chamber and subconjunctival hemorrhage have been reported to occur. 13 15 For patients requiring retinal surgery, warfarin therapy is normally discontinued so bleeding into the eye is not risked. 16 Patients who need retrobulbar anesthesia for ophthalmic procedures should also discontinue warfarin therapy before surgery. Gastrointestinal endoscopy In the absence of coagulation disorders, the risk of bleeding after mucosal endoscopic biopsy is negligible. However, the reported incidence of bleeding after endoscopic sphincterotomy ranges from 2.5% to 5%. 17 Delayed bleeding is of particular concern after endoscopic sphincterotomy, colonoscopy, and polypectomy, and anticoagulation therapy should be delayed accordingly after these procedures. 17 In a retrospective review of the management of oral anticoagulation therapy in 104 patients undergoing 171 endoscopic procedures, there were no thromboembolic or bleeding events associated with the continuation of warfarin therapy during procedures with low bleeding risk (eg, upper endoscopy) or with stopping warfarin therapy during procedures with a high bleeding risk (eg, polypectomy). 18

American Heart Journal Volume 147, Number 1 Jafri 5 Prostate surgery Although transurethral resection of the prostate has been reported to have been performed safely in patients undergoing anticoagulation therapy with warfarin, 19 many clinicians believe that only transurethral laser ablation is safe to use during anticoagulation therapy. In a study of 10 patients receiving long-term warfarin therapy, transurethral laser ablation of the prostate gland was performed with no perioperative complications and no more than minimal blood loss during the procedure. 20 Small studies have reported that transurethral resection of the prostate can be conducted safely with a brief interruption oral anticoagulation therapy with periprocedural heparins. 21,22 Abdominal surgery There is a deficiency of data about abdominal surgery in patients undergoing anticoagulation therapy. The minimally invasive nature of laparoscopic cholecystectomy greatly reduces the potential for bleeding compared with open cholecystectomy, and a study of 4 patients reported no hemorrhagic complications with heparin anticoagulation therapy during this procedure. 23 After gastric resection, there is an increased tendency for postoperative bleeding when anticoagulation therapy is continued during surgery. 24 In patients undergoing major abdominal surgery, LMWH can be given periprocedurally and continued for at least 5 postoperative days; compared with the periprocedural use of UFH, there is less resultant postoperative major bleeding. 25 An alternative strategy is to use UFH in the hospital, because anticoagulation can be reversed with protamine sulfate in the event of bleeding, and then to discharge the patient while receiving LMWH at a therapeutic dose. There are currently very limited periprocedural bridging data available for patients undergoing major abdominal vascular or cardiac surgical procedures. 26 Neurosurgical procedures and neuraxial anesthesia or spinal puncture For patients receiving chronic anticoagulant therapy, particular caution is needed to prevent bleeding during neurosurgery. A normal INR is recommended before neurosurgery, and restarting anticoagulation therapy postoperatively may need to be delayed. 27 During elective neurosurgical procedures, physical methods of prophylaxis (graded compression stockings, intermittent pneumatic compression devices, or vena cava filters) are often used because of concerns about intracranial or spinal bleeding with anticoagulants. It should be noted that when neuraxial anesthesia or spinal puncture is used, patients who are undergoing anticoagulation therapy or scheduled to undergo anticoagulation therapy with LMWH for the prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis. Risk of thrombosis on stopping anticoagulation therapy The risk of thrombosis on stopping anticoagulation therapy is dependent on specific patient conditions, as outlined below. In addition, the risk of VTE is heightened by the prothrombotic risk of surgery itself, although there is no evidence that surgery increases the risk of arterial embolism in patients with atrial fibrillation or mechanical heart valves. 2 Dunn and Turpie carried out an analysis of 31 reports of the perioperative treatment of patients receiving oral anticoagulants and found arterial thromboembolism and stroke rates of 1.6% (95% CI, 1.0% 2.1%) and 0.4% (95% CI, 0% 0.7%) for all patients. Thromboembolic event rates with management strategy were 0.4% for the continuation of oral anticoagulant therapy, 0.6% for the discontinuation of oral anticoagulant therapy without administration of UFH, 0% for the discontinuation of oral anticoagulant therapy with the administration of iv UFH, 0.6% for the discontinuation of oral anticoagulant therapy with the administration of LMWH, and 8% for unspecified or unclear strategies. 28 Mechanical heart valves: different valves and their thrombogenic risk The average rate of major thromboembolism in patients with mechanical heart valves who are not given anticoagulant therapy is estimated to be 8%. There is evidence that anticoagulation therapy reduces this risk by 75%. 2,29 Thrombotic complications of mechanical heart valves include systemic embolization, most commonly resulting in stroke or myocardial infarction, and occlusive thrombosis of the prosthetic valve orifice, which usually manifests as congestive heart failure. 30 The risk of thrombosis is related to the type of heart valve replacement, the valve site, and a prior history of thrombosis. Mitral valve prostheses carry a greater risk of systemic embolism than aortic valves. 31 Valve design and construction materials also affect thrombotic risk (Table I). 30 The newer second generation aortic mechanical valves are associated with a lower frequency of thromboemboli than the older prostheses. 31 Atrial fibrillation From a periprocedural risk stratification standpoint, patients with atrial fibrillation are generally considered to be at a relatively low risk for thrombosis. Patients with non-valvular atrial fibrillation who do not receive

6 Jafri American Heart Journal January 2004 Table I. Thrombogenic risks associated with different heart valves and their position Valve position Valve type Thrombogenic risk on anticoagulant therapy (% per year) Thromboembolism Fatal Nonfatal Valve thrombosis Mitral Caged-ball 1.11 7.59 0.55 Mitral Tilting-disc 0.80 3.69 0.70 Mitral Bileaflet 0.00 3.60 0.00 Aortic Caged-ball 0.61 2.75 0.03 Aortic Tilting-disc 0.65 1.04 0.33 Aortic Bileaflet 0.00 0.70 0.00 Data taken from Heit. 30 antithrombotic therapy have an average risk of systemic embolism of 4.5% per year. 2 The risk can vary from 1% to 20%, on the basis of associated risk factors. Patients with atrial fibrillation at intermediate risk of thrombosis are often 75 years old and have no risk factors, or have diabetes mellitus, coronary artery disease, thyrotoxicosis, or a history of hypertension. Patients with atrial fibrillation who are considered to be at high risk for thromboembolism are 75 years and have a history of hypertension, left ventricular dysfunction, or 1 intermediate risk factor. 32 The risk of thrombosis also increases in patients with mitral stenosis, prosthetic heart valves, and heart failure. 27,32 Although individual patient risk should be determined by the clinician, patients with intermediate and high risk of thromboembolism are reasonable candidates for periprocedural bridging with LMWH. The general recommendation that patients with atrial fibrillation do not require periprocedural bridging may be very conservative. 32 Venous thromboembolism An incidence of deep vein thrombosis (DVT) diagnosed within the last month puts patients in a highrisk group for recurrent thromboembolism, but the risk declines rapidly in the following 3 months. 2 For example, the rate of VTE during the first month after an acute episode of VTE is 40% in the absence of oral anticoagulation therapy, and it drops to 10% after 2 to 3 months. Anticoagulation therapy reduces the risk by approximately 80%. 2 Independent risk factors for recurrent VTE include increasing age and body mass index, malignancy, and serious neurologic disease with extremity paresis. 30 Hypercoagulable states Patients with inherited or acquired thrombophilia who have had a recent thrombosis or who have a history of life-threatening thrombosis are at a particularly high risk of thrombosis when periprocedural anticoagulation therapy is withheld. These disorders, which lead to a hypercoagulable state, include factor V Leiden mutation, prothrombin gene mutation, antiphospholipid antibody syndrome (APS), systemic lupus erythematosus with cardiolipin antibodies, protein C deficiency, protein S deficiency, and antithrombin III deficiency. Serious perioperative complications such as recurrent thrombosis, catastrophic exacerbation, or bleeding may occur, despite prophylaxis. 33 To bridge or not Currently, there is little consensus on the appropriate perioperative management of anticoagulation for patients on long-term warfarin therapy. Individual patient risk-to-benefit must be assessed before choosing a therapeutic regimen. For patients at low risk for arterial embolism ( 5% per year), a conservative approach during surgical or invasive procedures is considered appropriate. It has been advocated that all patients except those at the highest risk can be treated without perioperative bridging. Accordingly, preoperative UFH therapy and warfarin withdrawal during hospitalization are recommended only for patients with artificial heart valves who are at high risk for systemic embolism, 34 for patients with an episode of acute VTE 3 months before surgery, or for patients with arterial embolism within 1 month before surgery. 2 However, the safety of this approach for the risk of arterial embolism has not been fully evaluated. 2 Generally, after stopping warfarin therapy, it takes approximately 4 days to reduce the INR from a steady value of 2.0 to 3.0 to 1.5 (at which point surgery can be safely carried out) and approximately 3 days to reach therapeutic INR after it is restarted (INR, 2.0). 35 When necessary, vitamin K can be given to reduce the INR more quickly after stopping warfarin therapy. In patients who require emergency surgery or an urgent reversal of warfarin anticoagulation therapy, coagulation factor replacement therapy with fresh frozen plasma can be used. 30 Temporary discontinuation of warfarin exposes the patient to a risk of thromboembolism equivalent to 1 day without anticoagulation before surgery and 1 day after surgery. 2 A few studies in the 1970s evaluated the risk of thromboembolism and hemorrhage with and without periprocedural anticoagulant bridging for patients with prosthetic heart valves who were undergoing non-cardiac surgery. In 1 study, patients with aortic valves were shown to be susceptible to hemorrhage when anticoagulation was maintained during surgery (3 episodes of major bleeding in 6 patients), but not to thromboembolism when anticoagulation was discontinued before the procedure and resumed 3 to 5 days

American Heart Journal Volume 147, Number 1 Jafri 7 after. In contrast, in 10 patients with mitral or combined valve prostheses, there were 2 fatal perioperative thromboemboli when anticoagulation therapy was discontinued. 36 The risk may be lower with the currently available mechanical heart valves. Cessation of anticoagulation therapy for 3 to 5 days appears safe in patients with aortic prostheses in sinus rhythm who require non-cardiac operations. This view was supported by a subsequent prospective study in which there were no episodes of thromboembolism in 18 patients with aortic valve prostheses who were undergoing 19 non-cardiac operations. 37 The incidence of thromboembolism in patients after mitral or combined valve replacement is relatively high and constitutes a major risk, requiring rapid postsurgical restoration of anticoagulation therapy with iv heparin. 37 A retrospective review of 159 patients with heart valve prostheses undergoing 180 non-cardiac operations found only 6 episodes of thromboembolism in patients in whom anticoagulation therapy was stopped for 2.9 days before and restarted 2.7 days after surgery. Most patients had Starr-Edwards caged-ball aortic prostheses. 38 Despite these reports supporting the safety of withholding warfarin anticoagulation therapy for patients with aortic heart valve prostheses who are undergoing noncardiac surgery, more than two-thirds of 473 Canadian physicians who took part in a national survey preferred and practiced the use of iv UFH preoperatively and postoperatively, regardless of the type of surgery or the location of the prosthetic valve. 39 In patients who are at a higher thrombotic risk, the risk of thromboembolic complications is felt to be great enough to require perioperative treatment with iv UFH while the warfarin therapy is at subtherapeutic levels. 2,37,39 Typically, although the INR is subtherapeutic, these patients require approximately 3 days of iv UFH administration before and after surgery. 40 Heparins in periprocedural bridging No randomized controlled trials have been conducted to assess the optimal dosage regimens or methods for converting patients from warfarin to LMWH administration perioperatively. There have been no rigorous studies conducted to examine the efficacy, safety, dosing, or timing issues associated with converting patients to warfarin therapy after perioperative thromboprophylaxis with LMWH. The currently available LMWH preparations do not have US Food and Drug Administration-approved indication for periprocedural bridging. Physicians need to be vigilant for potential complications such as valve thrombosis in patients receiving bridging therapy with LMWH. They may choose iv UFH therapy for patients with mechanical heart valves who are at high-risk for comorbidities until the results of large scale trials demonstrate the safety and efficacy of LMWHs. Traditionally, full-dose iv UFH has been the standard therapy for patients who need full anticoagulant protection before a procedure. 6 This is a complex and costly procedure requiring hospitalization. In this use, LMWHs offer an attractive alternative to UFH. LMWHs have substantially more predictable effects on the degree of anticoagulation than UFH, there is no need for laboratory monitoring, and they have good bioavailability when administered subcutaneously. This means that perioperative conversion from warfarin to LMWH therapy can be carried out in the outpatient setting. In addition, there is less bleeding risk, less ostopenia, and less risk of heparin-induced thrombocytopenia. 41 LMWHS in periprocedural bridging in non-cardiac procedures There are an increasing number of studies evaluating the benefits of periprocedural bridging with LMWH in place of UFH. Perioperative conversion from warfarin to LMWH therapy in the outpatient setting has been recommended for patients who are at high risk for thromboembolism. 27 There are no randomized clinical trials of the use of LMWH for periprocedural bridging. Several observational studies support the use of LMWH for periprocedural bridging; these studies are outlined below and are summarized in Table II. In 1997, Kadayifci and colleagues reported success with the use of the LMWH nadroparin for bridging therapy in 21 patients who were receiving oral anticoagulation therapy because of prosthetic heart valves and who were admitted to the hospital with gastrointestinal bleeding. Oral anticoagulation was discontinued for 2 to 8 days, and LMWH was started as thromboprophylaxis during diagnostic procedures. After treatment, oral anticoagulation therapy was restarted, and LMWH was discontinued at a therapeutic INR. There were no thromboembolic or major bleeding events in a 13-month follow-up period. 42 In a separate study of 20 patients receiving long-term anticoagulant therapy to minimize thrombotic risk from prosthetic heart valves, atrial fibrillation, or thrombophilia, warfarin was stopped 4 to 6 days before invasive procedures (colonoscopy, upper endoscopy, oral surgery, cardiac catheterization, cardiac surgery, vascular surgery, herniorrhaphy, arthroscopy, knee replacement, thyroid biopsy, epidural injection, and dilatation and extraction), and LMWH therapy was started 36 hours later. 43 The LMWH enoxaparin was given at a dose of 1 mg/kg/12 hours, stopped 12 to 18 hours before the procedure, and restarted at a mean of 13.5 hours after the procedure, once hemostasis was achieved. Warfarin was started after the procedure, and enoxaparin administration continued (1mg/kg/12

8 Jafri American Heart Journal January 2004 Table II. Clinical trials evaluating the efficacy of LMWHs as bridging therapy Citation Patient numbers Indication LMWH Dose used Kadayifci 1997 21 Mechanical heart valve Nadroparin 3075 IU od Berdagué 1999 110 Mechanical heart valve replacement Dalteparin 100 IU/kg bd Enoxaparin 100 IU/kg bd Nadroparin 100 IU/kg bd Spandorfer 1999 20 Mechanical heart valve, atrial Enoxaparin 1 mg/kg bd fibrillation, hypercoagulable state Galla 2000 60 Mechanical heart valve Enoxaparin 30 mg bd Montalescot 2000 208 Mechanical heart valve replacement Enoxaparin 1 mg/kg bd Nadroparin 87 IU/kg bd Roijer 2000 242 Cardioversion of atrial fibrillation Dalteparin 200 IU/kg od Tinmouth 2000 24 Mechanical heart valve, atrial Dalteparin 200 IU/kg od fibrillation, VTE Wilson 2001 47 Mechanical heart valve, atrial fibrillation, VTE, congestive heart Dalteparin 5000 IU od, 200 IU/kg od, or 120 IU/kg bd failure Johnson 2001 515 Mechanical heart valve, atrial fibrillation, VTE, stroke Dalteparin Enoxaparin 100 IU/kg bd 1 mg/kg bd Nutescu 2001 21 Hypercoagulable state, stroke Dalteparin 100 IU/kg bd Ferreira 2003 82 Mechanical heart valve Enoxaparin 1 mg/kg bd hours) until the INR was therapeutic. Bleeding or thrombotic complications did not develop in any patient during the procedure. Post-procedural bleeding complications, all soft-tissue bleeding, developed in 3 patients (1 patient had bleeding 3 days after herniorrhaphy at the incision site, and the other 2 patients had minor bleeding). No post-procedural thrombotic complications occurred. It was concluded that enoxaparin therapy might be an alternative method of periprocedural anticoagulation therapy for patients undergoing long-term warfarin therapy. Another study of LMWH as periprocedural bridging for patients with mechanical heart valves who were undergoing noncardiac surgical procedures also supported enoxaparin therapy as a safe, consistent strategy for preventing VTE in these patients. 44 A recent observational study of 82 patients with mechanical heart valves who had oral anticoagulant therapy withheld and substituted with enoxaparin (1mg/kg twice daily) periprocedurally reported 8 minor and 1 major bleeding events during LMWH treatment, and no clinically detected thromboembolic events during hospitalization or the 3-month follow-up period. 45 A prospective trial, designed to assess the feasibility of an outpatient periprocedural protocol with the LMWH dalteparin for anticoagulation therapy in patients undergoing long-term warfarin therapy, involved 24 patients. 46 Patients were receiving warfarin for a prosthetic heart valve, mitral valve disease with atrial fibrillation, or a recent episode of VTE and were converted to dalteparin in preparation for surgical procedures, including cardiac catheterization, eye surgery, dental extraction, abdominal and vascular surgery, knee arthroscopy, and tissue biopsy. Warfarin was discontinued 4 days before the procedure, and 200 IU/kg of sc dalteparin was given on the 2 mornings before the day of surgery, with the last dose at least 24 hours before surgery. Dalteparin was restarted, at the same dose, 12 to 24 hours after surgery and continued until the INR was therapeutic, and warfarin was reinitiated on the evening of surgery. There were 2 minor bleeding complications, and 1 patient experienced a transient ischemic attack after a coronary angiogram. Patients received an average of 5 days of dalteparin therapy and avoided 2 days of hospitalization before their surgery. There were no major bleeding complications or thrombotic complications caused by the protocol. The authors concluded that outpatient perioperative dalteparin therapy appeared feasible in patients who were at a high risk of thrombosis. A study of 47 patients who were at high risk of thrombosis and were receiving long-term anticoagulant therapy and undergoing surgery concluded that outpatient dalteparin use can reduce unnecessary hospital stays in the perioperative period while providing safe and effective anticoagulant management. 47 Warfarin treatment was stopped 5 days before surgery, and 1 of 3 dalteparin regimens (5000 IU sc daily, 200 IU/kg sc daily, or 120 IU/kg sc twice a day) was started and continued until 24 hours before surgery. Dalteparin was restarted 12 hours after surgery until the INR was within the normal therapeutic range. Two patients experienced a thromboembolic event, although it was thought that in both cases it was not caused by the

American Heart Journal Volume 147, Number 1 Jafri 9 LMWH regimen. Two patients had minor hemorrhages, but there were no major hemorrhages during the perioperative period. The most recent study to evaluate the use of outpatient LMWH (dalteparin and enoxaparin) involved 515 patients. Patients were receiving chronic warfarin anticoagulant therapy for mechanical valve replacement (n 209), other valve surgery (n 57), atrial fibrillation (n 134), stroke (n 58), VTE (n 40), thrombophilia (n 3), cardiomyopathy (n 6), and coronary artery disease with apical thrombus (n 8) and required a periprocedural interruption of therapy. 26,48 Procedures undertaken were general or urological surgery, dental extraction, invasive cardiac diagnostic procedure, eye surgery, cardiovascular surgery, and catheter insertion. Dalteparin (100 IU/kg sc twice daily; n 372) or enoxaparin (1 mg/kg sc twice daily; n 143) was started preoperatively after stopping warfarin therapy, with the last injection 12 hours before the procedure (LMWH administered a mean of 5 times), and restarted post-procedurally after 8 to 24 hours, until the INR was therapeutic (LMWH administered a mean of 5.2 times). Oral anticoagulant use was resumed 8 to 24 hours after the procedure. The mean number of days with no oral anticoagulant therapy was 6. There were no thrombotic complications. There were 2 major bleeding events, 17 minor bleeding events, and 22 reports of injection-site bruising. The authors suggested that LMWH administered in a fixed dose sc, on an outpatient basis, is a practical alternative to iv UFH during interruption of warfarin therapy. The aforementioned studies indicate that conversion from warfarin to LMWH therapy is safe and effective for patients who require antithrombotic periprocedural bridging and that LMWHs can be administered in an outpatient setting. 27,30,46 LMWHs in periprocedural bridging after mechanical heart valve replacement LMWHs have been shown to provide adequate anticoagulant cover until oral anticoagulation is fully effective after heart valve replacement with mechanical prostheses. A study by Berdagué and colleagues showed a low incidence of ischemic and hemorrhagic events in patients who received LMWH (dalteparin, nadroparin, or enoxaparin,100 IU/kg/12 hours) on day 2 after surgery for heart valve replacement, until a therapeutic INR was reached. The mean duration of LMWH treatment was 11 days. 49 A study of 208 patients by Montalescot et al 50 showed that therapeutic sc doses of enoxaparin and nadroparin after heart valve replacement (mean duration, 14 days) compared favorably with UFH; therapeutic anticoagulation was achieved by day 2 in 87% of patients receiving LMWH, but in only 9% of patients receiving UFH. LMWHs were also superior to UFH in that, on the last day of prescription, anti-xa activity was at a therapeutic level ( 0.5 IU/mL) in all patients, but supratherapeutic levels ( 1 IU/mL) in only 19% of patients, whereas in the UFH group, 62% of patients were overcoagulated. Enrolled in the trial were patients with a history of hypertension, prior heart failure, prior ischemic stroke, atrial fibrillation, left atrium or left ventricle thrombus, endocarditis, enlarged left atrium, or left ventricle thrombus. Although patients were not randomized, baseline characteristics were comparable in the 2 groups. The study showed that the use of LMWH during the high-risk postoperative period after heart valve replacement was at least as safe as UFH. LMWHs in pregnancy Warfarin can cross the placenta, and its use in the first trimester of pregnancy is associated with embryopathy that is characterized by nasal hypoplasia, stippled epiphysis, or both. 51 Heparins do not cross the placenta and are therefore safe for the fetus. However, several reports of heparin failure resulting in maternal thromboembolism and death have been reported. 52,53 When UFH is used in pregnancy in women with prosthetic heart valves, it should be administered at a dose of 35000 units twice daily, with close monitoring of activated partial thromboplastin time or heparin assays. LMWH should be given at a dose of 100 IU/kg twice a day to maintain an anti-xa level between 0.5 and 1.0 U/mL, 4 to 6 hours after injection. 54 Recent experience with LMWH suggests that, despite their advantages, these drugs, like UFH, are associated with maternal complications. Aventis and the US Food and Drug Administration have issued a warning against the use of enoxaparin in pregnant women with prosthetic heart valves. 55 This warning was made on the basis of valve thrombosis and maternal deaths reported with enoxaparin use in a randomized trial comparing enoxaparin with warfarin in pregnant women with prosthetic heart valves. Patients and physicians are faced with a dilemma, and this issue is widely debated, with views ranging from no use of heparins in pregnancy to use with careful monitoring, understanding the risks versus benefits of their use. 54,56,57 These options have been recommended: 1) warfarin use throughout pregnancy, with its potential fetal risks, changing to heparin use (UFH or LMWH) at 38 weeks, and inducing labor at 40 weeks of gestation; 2) sc heparin use throughout pregnancy, with its associated maternal risks; 3) sc heparin use in the first trimester of pregnancy, switching to warfarin therapy in the second trimester; and 4) substitution of warfarin

10 Jafri American Heart Journal January 2004 with iv UFH in the first 6 to 12 weeks and last 2 weeks of pregnancy. There are no good options to ensure the safety of both the mother and fetus. There is a need for standardization of protocols and registries to increase published reports of these different approaches and their attendant risks versus benefits. LMWHs in periprocedural bridging for coronary stent placement Periprocedural bridging for patients undergoing longterm anticoagulation therapy who require coronary artery stent placement is a common clinical challenge. Patients who are at a high risk for thrombosis are good candidates for preprocedural bridging with LMWH at a therapeutic dose. After the coronary intervention, a combination of aspirin and ticlopidine has been shown to be superior to either aspirin alone or aspirin and warfarin in preventing stent thrombosis. 58,59 In a pilot study, a regimen of LMWH, ticlopidine, and aspirin was shown to be more effective than warfarin in decreasing thrombosis and ischemic clinical events after stent placement. 60 Patients at a high risk for thrombosis normally receive a combination of aspirin, warfarin, and clopidogrel. Currently, there are no published data on the postprocedural antithrombotic regimens for patients receiving oral anticoagulant therapy who are undergoing stent placement. For patients at low to intermediate thrombotic risk, most clinicians withhold warfarin for 2 to 4 weeks while administering a combination of aspirin and clopidogrel. Patients at high risk for thrombosis normally receive aspirin and warfarin. LMWH is used as a bridge post-procedurally until the INR is therapeutic. LMWHs in periprocedural bridging during cardioversion The risk of thromboembolism is greatest early after the onset of atrial fibrillation and during cardioversion to normal sinus rhythm, whether with electrical or pharmacological means. 61 Patients who have had atrial fibrillation for more than 48 hours and who have not undergone adequate anticoagulation therapy are generally at increased risk of systemic thromboembolism or stroke if cardioversion to normal sinus rhythm is performed in the absence of anticoagulation therapy. 62 The current ACCP guidelines for patients with atrial fibrillation recommend oral anticoagulation therapy for 3 weeks before and 4 weeks after cardioversion. 61 Traditionally, anticoagulation therapy is with warfarin, with UFH to provide extra antithrombotic cover during cardioversion. 63 Roijer et al 64 reported that transesophageal echocardiography (TEE) screening to select patients with no atrial thrombus, no spontaneous echocardiographic contrast, and a left atrial appendage outflow velocity 0.25 m/sec and prompt cardioversion with adjunctive dalteparin allowed effective and safe cardioversion, without previous anticoagulation therapy. Patients (162 from a study population of 242) who underwent immediate cardioversion maintained sinus rhythm significantly better after 1 month than patients undergoing prolonged warfarin therapy and delayed cardioversion. In another study, 23 patients with atrial fibrillation were immediately given dalteparin (100 IU/kg twice daily), which was continued for 11 days, with early TEE and immediate cardioversion when no thrombus was present. 65 Sinus rhythm was achieved in 74% of patients after a median of 7 days. Dalteparin had provided effective anticoagulant cover during cardioversion. 63,66 The Assessment of Cardioversion Using Transesophageal Echocardiography II (ACUTE II) trial is currently underway. This trial will compare the feasibility and safety of a TEE-guided enoxaparin strategy with a TEEguided UFH strategy in patients with atrial fibrillation for a duration 2 days who are undergoing early electrical or chemical cardioversion. 67 The use of TEE with LMWH as a bridge to a therapeutic INR with warfarin in patients with atrial fibrillation who did not previously undergo anticoagulation therapy and who are undergoing cardioversion offers an opportunity for a more aggressive management of atrial fibrillation on an outpatient basis. 62 Currently, there are too few reports (and these involve a small number of patients) to offer clear recommendations for this clinical situation. LMWHs in bridging for patients with hypercoagulable states The feasibility and safety of dalteparin use as perioperative bridging therapy for patients with a documented hypercoagulable state (protein C deficiency, protein S deficiency, and APS) and a history of ischemic stroke who are undergoing invasive procedures were evaluated in a prospective study. 68 Warfarin therapy was stopped 4 days before surgery and restarted on the night of surgery, once hemostasis was achieved. Dalteparin (100 IU/kg, sc daily) was initiated 3 days before surgery, with the morning dose withheld on the day of surgery. After surgery, dalteparin administration was continued until a therapeutic INR was reached. No thromboembolic events occurred in the patients during a 3-month follow-up period, and there were no major bleeding events. All patients self-administered the dalteparin injections. Perioperative treatment of patients with APS who require a variety of surgical procedures is discussed in a review by Erkan and colleagues. 33 These authors recommend that perioperative strategies should be clearly identified before the surgical procedure, both pharma-

American Heart Journal Volume 147, Number 1 Jafri 11 cological and physical antithrombosis interventions should be vigorously used, periods without anticoagulation should be kept to a minimum, and any deviation from a normal course should be considered a potential disease-related event. LMWH bridging in protocols and doses The selection of patients as candidates for outpatient periprocedural bridging with LMWH requires that they, or their health care provider, be geographically accessible and able to understand and demonstrate proper technique for administering the drug subcutaneously. There must also be assurance of compliance with the therapy regimen. Patients with hematological disorders such as protein C, protein S, or antithrombin III deficiencies would need individual advice from a hematologist. Options for preoperative and postoperative anticoagulation strategies with LMWHs are given in Table III. A strategy for perioperative thromboembolic prophylaxis with LMWH for patients at high thrombotic risk is given on Table IV. Doses of LMWHs used for periprocedural bridging are given in Tables 2 and 5. Patients with APS and inherited thrombophilias should receive doses of LMWH in the higher range (eg, dalteparin 200 IU/kg daily) as a minimum administered dose to prevent undercoagulation. 33 Point-of-care testing Point-of-care prothrombin time (PT) measurements have the potential to simplify oral anticoagulation management. Several monitors compare favorably with traditionally obtained PT measurements. 69 In a randomized clinical trial of conventional versus self-testing groups, the latter strategy was associated with a lower rate of hemorrhagic complications. 70 Results from the Early Self-controlled Anticoagulation Trial (ESCAT) in Germany showed that INR values were more frequently in range in the self-managed group than in the group that received usual care. 71 A thorough understanding of the risks and benefits of periprocedural bridging, patient education, and dedicated staff will ensure optimal results. Point-of-care and self-testing can be incorporated into this practice. Caution for use of LMWHs in patients with renal insufficiency The dosing of LMWHs in patients with renal insufficiency or obesity is challenging. During prolonged use of LMWHs, there is potential for drug accumulation in patients with renal insufficiency. It may be safer to use UFH for thromboprophylaxis in patients with a creatinine clearance 30 ml/min. Collet et al have demonstrated that enoxaparin can be administered safely in Table III. Periprocedural anticoagulant options Preoperative anticoagulation options Admit to hospital 2 4 days preoperatively for therapeutic dose iv UFH Outpatient therapeutic dose sc LMWH Outpatient prophylactic dose sc UFH or LMWH Nothing else other than stopping warfarin preoperatively Postoperative anticoagulation options Therapeutic dose inhospital IV UFH until INR therapeutic UFH to be started 12 h postoperatively Early discharge home with therapeutic dose LMWH until INR therapeutic Prophylactic dose inhospital sc UFH/LMWH Nothing else other than restarting warfarin postoperatively Therapeutic dose IV UFH/sc LMWH is the dose recommended for treatment of VTE or acute coronary syndromes. Prophylactic dose sc UFH or LMWH is the dose recommended for prophylaxis for VTE. patients with unstable angina and renal insufficiency by lowering the dose and monitoring anti-xa activity. 72 The safety of this approach for patients requiring periprocedural thromboprophylaxis needs to be studied in prospective trials. Cost-effectiveness of periprocedural bridging with LMWHs A significant advantage of LMWH compared with UFH is that LMWH can be self-administered, at home, with no need for laboratory testing. 41 The cost of each additional day of hospitalization required for anticoagulation therapy has been calculated at $600,000 for each thromboembolic event averted in patients with prosthetic valves. 40 This cost could be significantly reduced with the outpatient use of LMWH for patients who otherwise do not require in-hospital treatment. A cost-modeling study comparing outpatient LMWH, inpatient UFH, continuous warfarin, and discontinuation of anticoagulation therapy for patients receiving longterm anticoagulant therapy and undergoing elective colonoscopy concluded that LMWH offers a convenient and economical solution to periprocedural anticoagulation therapy. 73 Varying risk category or LMWH cost in the sensitivity analysis had a negligible impact on overall costs. In a study of cost-effectiveness of dalteparin for periprocedural bridging, an average of 6.5 hospital days were avoided per patient. 68 This resulted in a cost saving of $3250 per patient treated with dalteparin. During TEE-guided cardioversion of atrial fibrillation, a cost benefit of $1353 per patient was estimated for the substitution of UFH with LMWH. 67 Limitation of studies The quality of reports on periprocedural thromboprophylaxis in patients receiving long-term anticoagula-

12 Jafri American Heart Journal January 2004 Table IV. Perioperative thromboembolic prophylaxis with LMWH for patients who are at high risk of thromboembolism Time of procedure Anticoagulant therapy LMWH INR Complete blood count 4 Days before surgery Discontinue Initiate LMWH Yes Yes 1 Day before surgery Discontinue LMWH 12 24h pre op Yes No Day of surgery Resume anticoagulant LMWH 12 h postop No No therapy Postoperative day 1 Continue until INR 1.9 No Yes Postoperative day 2 Yes Yes Postoperative day 4 Yes No Patients at high risk of bleeding can be given prophylactic dose of LMWH sc daily for 4 days starting the morning after the procedure. Patients at low risk of bleeding can receive therapeutic dose LMWH sc daily, starting the morning after surgery until INR 1.9. Table V. Prophylactic and therapeutic doses of LMWHs LMWH Prophylactic dose Therapeutic dose Dalteparin 5000 IU od 100 IU/kg/12 h, 200 IU/kg/24 h Enoxaparin 40 mg od 1 mg/kg/12 h, 1.5 mg/kg/24 h Nadroparin 38 IU/kg od 87 IU/kg/12 h Tinzaparin 4500 IU od 175 IU/kg/24 h tion therapy is generally poor, and therefore, recommendations are weak (level IIC). The details of comorbid conditions that clinicians have used to stratify bleeding risk and thromboembolic risk is often not stated. In most reports, the sample sizes are small, the details of anticoagulation administration and discontinuation are not described, and the duration of follow-up is not clearly stated. There are ongoing registries and trials to address some of these issues; a prospective registry is evaluating the clinical outcomes of patients undergoing preoperative or postoperative bridging with UFH or LMWHs, and another, multicenter, prospective study is evaluating the role of LMWH use for periprocedural bridging in patients receiving long-term anticoagulation therapy. Recommendations Although the literature is limited, the following recommendations are made on the basis of available evidence. Because the recommendations for LMWHs are for off-label use, informing the patient may be a critical part of the use of these agents in this setting. Patients with moderate to high risk of bleeding from the surgical procedure Low risk of thromboembolism. Examples: atrial fibrillation without multiple intermediate factors, VTE without high-risk features Stop warfarin 4 days before surgical procedure Use prophylactic doses of UFH or LMWH sc when a surgical procedure increases the risk of thrombosis Resume warfarin on the day of surgery. Intermediate risk of thromboembolism. Examples: atrial fibrillation and age 65 years, diabetes mellitus, coronary artery disease, or hypertension; mechanical aortic heart valves in sinus rhthym without heart failure or prior thromboemboli; DVT 3months without high-risk features Stop warfarin 4 days before surgery Optional use of outpatient therapeutic dose sc LMWH preoperatively and postoperatively Postoperative use of prophylactic dose sc UFH or LMWH (when the therapeutic dose is not administered) Resume warfarin on day of surgery. High risk of thromboembolism. Examples: atrial fibrillation with prior thromboembolism, heart failure, prosthetic heart valve, mitral stenosis; bileaflet mitral heart valve with atrial fibrillation or heart failure without prior thromboembolism; aortic mechanical heart valve with prior thromboembolism, atrial fibrillation, or heart failure; DVT 3 months with high-risk features (active malignancy, multiple episodes of VTE, known thrombophilic state) Stop warfarin 4 days before surgery Use therapeutic dose LMWH sc preoperatively and postoperatively Discontinue LMWH 12 to 24 hours before surgery, depending on the LMWH preparation and dosing schedule Resume therapeutic dose iv UFH or LMWH sc 12 hours postoperatively Resume warfarin on the day of surgery. Very high risk of thromboembolism. Examples: multiple heart valves; non-bileaflet mechanical heart